GB1576550A - 21,21-dihalo steroids - Google Patents

Description

PATENT SPECIFICATION ( 11) 1576550

( 21) Application No 31615/77 ( 22) Filed 27 July 1977 ( 31) Convention Application No 711 042 ( 19) ( 32) Filed 2 Aug 1976 in ( 33) United States of America (US) If ( 44) Complete Specification published 8 Oct 1980 ( 51) INT CL 3 C 07 J 71/00; A 61 K 31/58 ( 52) Index at acceptance C 2 U 2 4 A 1 B 4 A 2 A 4 A 2 X 4 B 2 B 4 B 2 X 4 C 1 OA 4 C 11 4 C 4 B 4 C 4 X 4 C 5 4 CX 4 D 1 4 DX 4 N 6 B 4 N 6 Y 4 N 9 5 6 A 1 6 B 6 C 6 E 8 A 1 ( 54) 21,21-DIHALO STEROIDS ( 71) We, SYNTEX (U S A) INC, a Corporation organised under the laws of the State of Delaware, United States of America, of 3401 Hillview Avenue, Palo Alto, California 94304, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following 5

statement:-

This invention relates to a new class of 16 a,17 a-acetonide steroids which are 21,21-dihalo substituted More specifically they are compounds which are 21,21dihalo 16 a, 17 a-isopropylidenedioxypregna 1,4-diene-3,20 diones and the corresponding pregn-4-enes which may have a 6 a-fluoro or chloro substiuent, a 9 a 10 fluoro, chloro or bromo substituent, and an 1 lp 3-hydroxy substituent or 1 l 1-chloro substituent The compounds of the invention are useful as topical antiinflammatories The invention also relates to a process for making the compounds of this invention which comprises formylating at the 21 position a A/49114 steroid having either one halo substituent or no halo substituents at the 21 position, 15 halogenating, subsequently deformylating, and reacting at the 9 ( 11) double bond to form the compounds of the invention.

It is known from U S 3,236,866 to Ringold and Edwards that 21,21-difluoroA'-pregnenes are useful as progestational agents and as such exhibit antiandrogenic, anti-estrogenic and anti-gonadotrophic activity It is also known from 20 U.S 3,681,405 patented I August 1972 to Laurent et al (British Specification No.

1317184) that certain 21,21-dichloro steroids have anti-inflammatory activity The compounds are represented by the formula CH CL 2 I C=O F wherein 25 R 1 is hydrogen or chlorine; R 2 is hydrogen, fluorine or methyl; R 3 is hydrogen or methyl; R 4 is hydrogen or a free or esterified hydroxy group; and C___ _ C 2 represents a single or double bond joining carbon atoms at the I and 30 2 position.

It is further known that 2121-diiodo, -dibromo and -dichloro steroids are useful as intermediates in preparation of certain steroid compounds See for example Canadian patent 769,025; French patent 1,243,528; U S patent 2, 715,621; U.S patent 2,752,366; and German patent DT 2225658, the latter patent disclosing the 21,21 -diiodo compounds which are useful for the preparation of triamcinalone, fluocinolone, dexamethasone, betamethasone, and paramethasone.

One aspect of this invention is a compound represented by the formula 5 Xt I W C-%) 0 = O 2,'C H 3 X wherein X is fluoro, chloro or hydrogen; X' is hydrogen, fluoro, chloro or bromo; X 2 is hydroxy or may be chloro when X' is chloro; 10 X 3 and X 4 are independently fluoro, chloro, or bromo; and the broken line between C-I 1 and C-2 indicates that the bond between C-I and C-2 is a single or a double bond Of the compounds encompassed by the generic formula, the preferred compound is selected from those represented by formula (I) wherein X 3 and X 4 are independently fluoro or chloro and X, X', X 2 and 15 the broken line are as previously defined.

Another aspect of this invention is a method of treating an inflamed condition in non-human mammals which method comprises topically applying at least one compound to the inflamed condition.

Still another aspect of the invention is a topical anti-inflmmatory composition 20 which comprises a compound of this invention formulated with a suitable, pharmaceutically acceptable carrier.

Another aspect of this invention provides processes for producing 21,21dihalosteroids, as defined in the appended claims and as described and illustrated below 25 Certain of the compounds hereof may be obtained by the steps of:

(a) reacting a formylating agent with a compound represented by the formula C 1 N 2 F C=O _ 0,,-,Cl X wherein X is fluoro, chloro or hydrogen, to form a compound represented by the formula 30 1,576,550 1,576,550 0 ' X FC_=COHC=O ( 111) wherein X is previously defined; (b) reacting the compound represented by formula ( 111) with a halogenating agent to form a compound represented by the formula X 3 c FCH O I O' ( 1 v) wherein X is previously defined and X 3 is chloro or bromo (c) reacting the compound represented by formula (IV) with a deformylating agent to form a compound represented by the formula FCX 3 C=O (v) wherein X and X 3 are defined previously (d) treating the compound of formula (V) with a suitable reactant or reactants, as described hereinafter, to form a 21-fluoro-21-halo compound of this invention represented by formula (I) wherein X, XI, X 2 and X 3 are previously defined; and (e) optionally, if the A 4 steroids of the invention are desired, reducing the is Cl-C 2 double to a single bond.

Alternatively, the z 4 steroids may be obtained by proceeding through steps (a)-(d) but substituting an ethylene ketal derivative for the compound represented by formula (II), namely a compound represented by 1.576,550 O X a) then hydrolyzing the ketal to form a 21-fluoro-21-halo-A 4 steroid of formula (I).

The A 11,4 steroid of formula (I) is thereafter obtained by forming an unsaturated bond between C, and C 2 as discussed hereafter.

The 21,21-difluoro steroids of the invention are obtained by reacting a 5 compound represented by formula (V) with a fluorinating agent to substitute a fluoro for the X 3 group at the 21 carbon.

The 21,21-dichloro or 21,21-dibromo steroids of the invention are prepared by (a) formylating an appropriate 16 a,17 a-isopropylidenedioxypregna 1,4,9 ( 11)triene-3,20-dione to form the corresponding compound having a hydroxy 10 methylene group at the 21 position; (b) halogenating the product from the previous step to form the corresponding 21,21 -dihalo-21 -formyl-steroid; (c) deformylating to form the corresponding 21,21-dihalo compound; (d) treating the resulting product to add the desired substituents at 9 aand 11 I 15 positions; and (e) optionally, reducing the A' bond.

The 21-bromo-21-chloro steroids are similarly prepared except that in step (b) immediately above, the compound is chlorinated (or brominated) to give the 21chloro (or 21-bromo)-21-formyl steroid then brominated (or chlorinated) to give 20 the 21 -chloro-21-bromo-21 -formyl steroid.

The compounds of this invention show high topical anti-inflammatory potential and low systemic effects such as thymolytic activity and skin thinning effects.

Compounds falling within the scope of the invention are those represented by 25 formula (I) wherein X is hydrogen, fluoro, or chloro; X' is hydrogen, fluoro, chloro, or bromo; X 2 is hydroxy or may be chloro when X' is chloro; X 3 and X 4 are independently fluoro, chloro or bromo; and 30 the broken line between C-I and C-2 represents a single or a double bond.

Thus compounds falling within the scope of the claims include the following compounds which are named as 16 a,17 a-isopropylidenedioxypregna-l,4diene3,20-diones or 16 t,17 a-isopropylidenedioxypregn-4-ene-3,20-diones, with the substituents on the 6 a-,9 a-,113-,21-positions being named in alphabetical order: 35 6 ca,21,21-trifluoro 11 3-hydroxy-16 a,17 a-isopropylidenedioxypregna 1,4diene-3,20-dione; 21-chloro-6 a,21-difluoro-11 3-hydroxy-16 a, 17 oisopropylidenedioxypregna1,4-diene-3,20-dione; 21-bromo-6 a,21-difluoro 1 lp 3-hydroxy-16 a,17 aisopropylidenedioxypregna 40 1,4-diene-3,20-dione; 21,21-dichloro-6 a-fluoro-11/3-hydroxy-16 oa,17 aisopropylidenedioxypregna1,4-diene-3,20-dione; 21 -bromo-21-chloro-6 a-fluoro 11/3-hydroxy-16 a,17 a-isopropylidenedioxypregna 1,4-diene-3,20-dione; 45 21,21 -dibromo-6 oa-fluoro 1 1/-hydroxy 16 a, 17 aisopropylidenedioxypregna1,4-diene-3,20-dione; 6 a,9 a,21,21 -tetrafluoro 1/3 l-hydroxy 1 6 a, 17 aisopropylidenedioxypregna 1,4diene-3,20-dione; 1,576,550 5 21 -chloro-6 oa,9 a,2 I -trifluoro 11 /3-hydroxy I 6 a, 17 aisopropylidenedioxypregna I 1,4-diene-3,20-dione; 21 -bromo-6 a,9 a,2 I -trifluoro I 1/3-hydroxy 16 a, 17 aisopropylidenedioxypregna-1,4-diene-3,20-dione; 21,21 -dichloro-6 a,9 a-difluoro I 1 13-hydroxy I 6 a, 17 aisopropylidenedioxy pregna I 1,4-diene-3,20-dione; 21 -bromo-21 I-chloro-6 a,9 a-difluoro-11 13-hydroxy 16 a,17 crisopropylidenedioxypregna 1,4-diene-3,20-dione; 21,21 -dibromo-6 a,9 cr-difluoro I 1/3-hydroxy I 6 at, I 7 aisopropylidenedioxypregna I 1,4-diene-3,20-dione; 10 9 a-chloro-6 a,21,21 -trifluoro I 1/3-hydroxy 16 a, I 7 aisopropylidenedioxypregna I 1,4-diene-3,20-dione; 9 a,21 I-dichloro-6 a,21 I-difluoro-11 /3-hydroxy-1 16 ai,1 17 ctisopropylidenediox'ypregna I 1,4-diene-3,20-dione; 21 -bromo-9 a-chloro-6 a,21 I-difluoro-l I 11/-hydroxy 16 a,1 17 aisopropylidene 15 dioxypregna I 1,4-diene-3,20-dione; 9 a,21,21 -trichloro-6 a-fluoro I 1 13-hydroxy I 16 a, 1 7 aisopropylidenedioxypregna 1,4-diene-3,20-dione:

6 a-chloro-21,21 -difluoro I 1/3-hydroxy 16 a, I 17 aisopropylidenedioxypregfla1,4-diene-3,20-dione; 20 9 a, 11/3,21 -trichloro-6 a,2 1 -difluoro I 6 a, I 7 aisopropylidenedioxypregna 1,4diene-3,20-dione; 21 -bromo-9 a, I 1 3-dichloro-6 a,2 1 -difluoro 16 a, I 7 aisopropylidenedioxypregna 1,4-diene-3,20-dione; 9 a,l 11/,21,21 -tetrachloro 16 a,17 a-isopropylidenedioxypregna-1 I,4diene-3,20 25 dione; 6 a-chloro-21,21 -dicluro 11 /3-hydroxy 16, 1 7 aisopropylidenedioxypregna 1,4diene-3,20-dione; 6 a,2 I -dichloro-2 1 -fluoro I 1/3-hydroxy 1 6 a, I 7 aisopropylidenedioxypregna1,4-diene-3,20-dione; 30 21 -bromo-6 a-chloro-2 1 -fluoro I 1 13-hydroxy I 16 a, 17 aisopropylidenedioxypregna I 1,4-diene-3,20-dione; 6 a,21,21 -trichloro 1 1/3-hydroxy 16 a, I 7 a-isopropylidenedioxypregna 1,4diene-3,20-dione; 6 a-chloro-9 a,21,21 -tetrafluoro I 1/3-hydroxy 1 6 a, 17 aisopropylidenedioxy 35 pregna 1,4-diene-3,20-dione; 6 a,21 I -dichloro-9 a,2 I -difluoro I 1/3-hydroxy I 6 a, 17 aisopropylidenedioxypregna 1,4-diene-3,20-dione; 21 -bromo-6 a-chkoro-9 a,2 1 -difluoro 1 1/3-hydroxy 16 a, 17 aisepropylidenedioxypregna I 1,4-diene-3,20-dione; 40 6 a,21,21 -trichloro-9 a-fluoro 1 1/3-hydroxy I 16 a, I 17 aisopropylidenedioxypregna 1,4-diene-3,20-dione; 6 a,9 a-dichloro-21,21 -difluoro 1 1/3-hydroxy 16 a, 17 cisopropylidenedioxypregna 1,4-diene-3,20-dione; 6 ar,9 ar,2 I -trichloro'-2 I -fluoro I 1/3-hydroxy 1 6 ar, 17 aisopropylidenedioxy 45 pregna I 1,4-diene-3,20-dione; 21 -bromo-6 a,9 ar-dichloro-2 1 -fluoro 1 1/3-hydroxy 16 a, 17 aisopropylidenedioxypregna 1,4-diene-3,20-dione; 6 ar,9 a,21,21 -tetrachloro 1 1/3-hydroxy 16 ot, 17 arisopropylidenedioxypregna 1,4diene-3,20-dione; 50 6 ar,9 ar, 11 /3-trichloro-2 1,21 l -difluoro 16 c, 17 aisopropylidenedioxypregna 1,4diene-3,20-dione; 6 cr,9 ar, 11/3,21 -tetrachloro-2 1 -fluoro 16 cr, I 7 arisopropylidenedioxypregna 1,4diene-3,20-dione; 21 -bromo-6 ar,9 a, 11 /3-trichloro-2 I -fluoro 16 a, 17 aisopropylidenedioxypregna 55 I 1,4-diene-3,20-dione; 6 ar,9 cr, 11/3,21,21 -pentachloro 16 c, 17 a-isopropylidenedioxypregna 1, 4-diene3,20-dione; 9 ar,21,21 -trifluoro 1 1/3-hydroxy 16 c, 17 c-isopropylidenedioxypregna 1,4diene-3,20-dione; 60 21 -chloro-9 a,2 1 -difluoro 11 /3-hydroxy I 6 cr, 17 arisopropylidenedioxypregnaI 1,4-diene-3,20-dione; 21,21 -dichloro-9 ar-fluoro I 1/3-hydroxy 1 6 cr, 17 arisopropylidenedioxypregnaI 1,4-diene-3,20-dione; 6 1,576,550 6 9 a, 11 /-dichloro-21,21 -difluoro 16, 17-isopropylidenedioxypregna 1,4diene3,20-dione; 9 a, I 1/3,2 1 -trichloro-2 1 -fluoro 16 a, 17 aisopropylidenedioxypregna 1,4-diene3,20-dione; 9 a, 1 1/3,21,21 -tetrachloro-6 a-fluoro I 16 a, I 17 aisopropylidenedioxypregna 1,4 5 diene-3,20-dione; 9 ar-bromo-6 a 21,21 -trifluoro- 11 11/-hydroxy 16 a, 17 aisopropylidenedioxypregna 1,4-diene-3,20-dione; 9 a-bromo-6 a-chloro-21,21 -difluoro 11 /3-hydroxy 1 6 a, 1 7 aisopropylidenedioxypregna 1,4-diene-3,20-dione; 10 9 a-bromo-21,21 -difluoro 1 1 13-hydroxy 1 6 a, 17 aisopropylidenedioxypregna1,4-diene-3,20-dione; 9 a-bromo-2 1 -chloro-6 a,2 1 -difluoro 1 1/3-hydroxy 1 6 a, 17 aisopropylidenedioxypregna 1,4-diene-3,20-dione; 9 a-bromo-21,21 -dichloro-6 a-fluo'ro 1 1/3-hydroxy 1 6 a, 17 aisopropylidene 15 dioxypregna 1,4-diene-3,20-dione; 9 a-bromo-6 a 21,21 -trifluoro 1 1/3-hydroxy 16 a, 17 aisopropylidenedioxypregna 1,4-diene-3,20-dione; 21,21 -difluoro 1 1/3-hydroxy 1 6 a, 17 a-isopropylidenedioxypregna 1,4diene3,20-dione; 20 9 a-bromo-21-chloro-21-fluoro 1 1/3-hydroxy-1 16 a,17 aisopropylidenedioxypregna 1,4-diene-3,20-dione; 21,21 -dichloro-6 a 1-fluoro 1 1/3-hydroxy 1 6 a, 1 7 aisopropylidenedioxypregna1,4-diene-3,20-dione; 21,21 -dichforo-6 a,9 a-d fluoro-'1-1/3 hydroxy 16 a,f 17 aisopropy'lidenedioxy 25 pregn-4-ene-3,20-dione; 21 -bromo-2 1 -chloro-6 a,9 a-difluoro 1 1/3-hydroxy 16 a, 17 aisopropylidenedioxypregn-4-ene-3,20-dione; 6 a,21,21 -trifluoro-9 a-chloro 1 1/3-hydroxy 16 a, I 17 aisopropylidenedioxy 3 pregn-4-ene-3,20-dione; 3 21 -bromo-9 a-chloro-6 ar,2 1 -difluoro 1 1/3-hydroxy 16 a, 17 aisopropylidenedioxypregn-4-ene-3,20-dione; 9 a,21,21 -trichloro-6 ar-fluoro 1 1/3-hydroxy 16 a, 17 jaisopropylidenedioxypregn-4-ene-3,20-dione; 6 al,2 1 -trifluoro-9 a, 11 /3-dichloro 16 a, 17 aisopropylidenedioxypregn-4-ene 35 3,20-dione; 9 a, 11/3,21 -trichloro-6 a,2 1 -difluoro 16 a, 17 aisopropylidenedioxypregn-4-ene3,20-dione; 21 -bromo-9 a, 1 1 13-dichloro-6 a,2 1 -difluoro 1 6 a, 17 aisopropylidenedioxypregn-4-ene-3,20-dione; 4 9 a, 11/3,21,21 -tetrachioro 1 6 a, 17 a-isopropylidenedioxypregn-4-ene-3, 20dione; 6 ar-chloro-21,21 -difluoro 1 1/3-hydroxy 16 a, 17 aisopropylidenedioxypregn-4ene-3,20-dione; 6 a,21-dichloro-21-fluoro 1 1/3-hydroxy 16 a,17 aisopropylidenedioxypregn-4 45 ene-3,20-dione; 6 a-chloro-9 a,21,21 -trifluoro 1 1/3-hydroxy 16 a,1 17 aisopropylidenedioxypregn-4-ene-3,20-dione; 6 a,2 1 -dichloro-9 a-2 1 -difluoro 1 1/3-hydroxy 16 a, 17 aisopropylidenedioxypregn-4-ene-3,20-dione; 50 21 -bromo-6 a-chloro-9 a,2 1 -difluoro 1 1/3-hydroxy 1 6 a, 17 a-isopropylidenedioxypregna 1,4-diene-3,20-dione; 6 a,21,21 -trichloro-9 a-fluoro 1 1/3-hydroxy 16 a, 17 aisopropylidenedioxypregn-4-ene-3,20-dione; 6 al,9 a-dichloro-21,21 -difluoro 1 1/3-hydroxy 16 a, I 17 aisopropylidenedioxy 5 pregn-4-ene-3,20-dione; 6 a,9 a-2 1 -trichloro-2 1 -fluo-ro-1 1/3-hydroxy 16 a, 17 aisopropylidenedioxypregn-4-ene-3,20-dione; 21 -bromo-6 a,9 a-dichloro-2 I -fluoro 1 1/3-hydroxy 16 a, 17 aisopropylidenedioxypregn-4-ene-3,20-dione; 60 6 a,9 a,21,21 -tetrachloro I 1/3-hydroxy 1 6 a, I 17 aisopropylidenedioxypregn-4ene-3,20-dione; 6 a,9 a, 1 If/-trichloro-21,21 -difluoro I 16 a, 17 aisopropylidenedioxypregn-4-ene3,20-dione:

6 a,9 a,l 1/P,21-tetrachloro-21-fluoro-16 cr,17 aisopropylidenedioxypregn-4-ene3,20-dione; 6 ac-bromo-21 -chloro-9 a,21-difluoro 1 1/p-hydroxy 16 a,17 arisopropylidenedioxypregna 1,4-diene-3,20-dione; 6 a,21,21 -trifluoro-I lp/-hydroxy 16 a, 17 a-isopropylidenedioxypregn-4ene 5 3,20-dione; 21-chloro-6 a,21-difluoro I lp/-hydroxy 16 ca, 17 aisopropylidenedioxypregn-4ene-3,20-dione; 21,21 -dichloro-6 a-fluoro-I /l-hydroxy 16 a, 17 aisopropylidenedioxypregn-4ene-3,20-dione; 10 6 a,9 ca,21,21 -tetrafluoro 1 lp/-hydroxy 16 ac,17 aisopropylidenedioxypregn-4ene-3,20-dione; 21 -chloro-6 a,9 cr,21 -trifluoro 1 lp/-hydroxy 16 a, 17 aisopropylidenedioxypregn-4-ene-3,20-dione; and other A 4 steroids corresponding to the A,'4 steroids named hereinbefore 15 Of the compounds broadly set forth above, the group that is particularly valuable and therefore preferred includes the compounds represented by formula (I) wherein X 3 and X 4 are each independently chosen from fluoro or chloro and X, X', X 2 are the broken line between Cl and C 2 are as described in this section hereinbefore An especially preferred subgroup is that wherein X is fluoro; X' is 20 fluoro or chloro; X 3 is fluoro; X 4 is fluoro or chloro; and X 2 is as previously described.

The essence of the process aspect of this invention is premised on the discovery that certain known 16 a, 17 a-isopropylidenedioxypregna 1,4,9 ( 1 1)-triene3,20-diones compounds which are substituted by one fluoro atom at the 21 position 25 or have no fluoro at the 21 position can be 21-formylated, halogenated and deformylated to form novel intermediates from which the novel antiinflammatory compounds of this invention are obtained Reaction Scheme A exemplified one facet of the process for preparing the compounds of this invention In this reaction scheme the wavy line indicates that the rest of the steroid molecule remains 30 unchanged.

1.576550 8157 5 I-C-H (i v) O O F-c-? (I at) (ii') (vl) CC) (I) X One aspect of the process of this invention comprises (a) treating a compound (II) which is substituted with a fluorine atom on the 21 carbon of the steroid chain with a formulating agent to form a compound of formula (III), (b) treating the compound of formula (III) with a suitable halogenating agent to form a 21fluoro 5 21-halo compound (IV) also having a formul group attached to C 2,; and (c) deformylating the compound, i e, the formylgroup is removed to form a compound indicated as formula (V).

The compound of formula (V) may be treated with a suitable chlorinating agent to form a compound of formula (Ia), or may be treated to form a 9 a, 1 1/P 10 bromhydrin of formula (Tb) which in turn is epoxidized then hydrofluorinated to form a 9 a,1 1 -fluorhydrin of this invention represented by formula (Ic).

576550 v C-14 1 F 't i oyd 1 0 (a) In The first step of the process of this invention the starting material, a 16 a, 1 7 a-isopropylidenedioxypregna 1,4,9 ( 11 1)-triene-3,20-dione: which is substituted at the 21 position with a fluoro substituent, and preferably with a 6 afluoro or 6 a-chloro substituent, is mixed with a suitable hindered base such as Niso-propyl-N-lithium-cyclohexylamine (formed by reacting isopropylcyclo 5 hexylamine with n-alkyl lithium in an appropriate aprotic solvent such as a mixture of tetrahydrofuran and hexamethylphosphoric triamide or other suitable ethers such as glyme, dioxane, tetrahydropyran (THP), and the like), N-lithiumdiisopropylamine or N-lithium bis-l, 1, -trimethylsilylamine The reactants are stirred together preferably in an inert atmosphere such as nitrogen or argon at 10 temperatures from about 10 to 50 C preferably at about 20 -25 C for 5 to 24 hours A suitable formylating agent such as ethyl formate is added and the reaction continued for a time sufficient to form a compound represented by formula (III).

Generally this will be about two to 10 hours, preferably about 4 or 5 hours The resulting product can then be extracted and crystallized using methods well known 15 in the art for this particular process.

(b) Once a reaction product represented by formula (III) is obtained, it is reacted with at least an equimolar amount of a halogenating agent, i e (i) a suitable chlorinating agent such as copper chloride with lithium chloride, t-butyl hypochlorite, sulfuryl chloride and the like, (ii) a suitable brominating agent such as 20 cupric bromide and the like or (iii) a suitable fluorinating agent such as trifluoromethyl hypofluorite, perchloryl fluoride, and the like, in a suitable solvent such as DMF, chloroform or THF Generally the reaction will take place at a temperature of about 25 to 100 C, preferably about 40 to 50 C for the first part of the reaction then 70 to 90 C for the latter part of the reaction The reaction will 25 be completed in about 2 to 10 hours, preferably about 3 hours at the lower temperature and 1 hour at the upper temperature.

(c) The resulting 21-fluoro-21-chloro (-21-bromo or 21-difluoro)-21formyl steroid (IV) is reacted with a molar excess of a deformylating agent such as an alkali metal hydroxide (e g sodium or potassium hydroxide) or an alkaline earth 30 hydroxide (e g barium hydroxide) in a suitable solvent such as ethanol, methanol, ether or water, or mixtures thereof This reaction will take place generally at about -10 to + 10 C, preferably at O C for a period of time sufficient to complete the reaction which is generally about 1 to 5 hours, preferably about 2 to 3 Purification and recrystallization can be done using procedures known in the art 35 An alternative method for preparing a 21,21-difluorosteroid such as (Id), (Ie) or (If) is to treat the resulting product if a 21-bromo or 21-chloro is present, with a suitable fluorinating agent such as tetramethylammonium fluoride in an appropriate solvent such as sulfonane at the appropriate temperature, for example about 40 to 120 C, preferably about 70 to 90 C for a period of time sufficient to complete the 40 reaction, i e generally about 2 to 10 hours, preferably about 2 to 3 After purification the resulting 21,21-difluoro compound (VII) (or the 21,21mixed halogen compound) is futher treated to form the corresponding 9 a,1 lpdichloro compound represented by formula (Id) (or formula (Ia) in the case of the 21,21mixed halogen compound) by chlorinating across the double bond between C9 45 and C 1 The chlorination step may be carried out using procedures known in the art, e g see "Steroids" 5, 615-35 ( 1965) by Heller et al.

Generally chlorine gas is bubbled through a solution of the reactant in a chlorinated hydrocarbon such as methylene dichloride in the presence of a suitable base catalyst such as pyridine Generally the addition takes no more than a few o 50 minutes as about 20 0-30 C.

A 9 a-fluoro-llp-hydroxy compound represented by formulae (Ic) or (If) is formed by epoxidixing the bond between the C-9 and C 1 carbons in formulae (V) or (VII) the epoxidation is a two step procedure wherein a compound of this invention represented by formulae (Ib) or (Ie) is prepared by reacting (V) or (VII) 55 with dibromantin along with a dilute perchloric acid solution In this step, an intermediate having 9 a-bromo 11/3-hydroxy substituents on the steroid structure (Ib) or (Ie) is first formed which may be readily purified using procedures well known in the art This material (either crude or pure) is then dehydrobrominated using for example isopropyl alcohol and potassium acetate at reflux temperature 60 for a time sufficient to form the epoxide as indicated in formula (VI) and (VIII).

The resulting epoxide compound is purified then reacted with a hydrohalogenating agent such as hydrofluoric or hydrochloric acid to form a 9 a-haloI l/3-hydroxy compound of this invention Such hydrohalogenating procedures are well known in the art See for example Organic Reaction In Steroid Chemistry, Vol I, 65 1,576,550 edited by J Fried and J Edwards, Chap 8, Van Nostrand Rheinhold ( 1972) By reacting the compound represented by formulae (Ib) and (Ie) with, e g, tributyltin hydride in a suitable solvent such as THF, other compounds of the invention represented by the following formulae may be respectively obtained:

(cl) := O U ' X O ox (-e') O O Generally the conversion is implemented by irradiation in the presence of azobisisobutyronitrile.

The 21,21-dichloro, 21-bromo-21-chloro and 21,21-dibromo steroids of the invention are prepared by a process similar to that set forth in Reaction Scheme A, but instead of a 21-fluoro steroid as a starting material, a 16 a,17 caisopropylidenedioxypregna-l,49 ( 1 l)-triene-3,20-dione is employed as set forth in Reaction Scheme B In this reaction scheme the wavy lines in formulae (IIIB), (IIIC) , (IVB) and (VB) indicate that the remainder of the steroid structure (i e positions 1-19) is the same at that depicted in formula (IIB).

l HC=-CV Dh 1 C_.=O ( 11 5) C= O (V 8) t H X 4 HCH O > I C.FO l Cac) l I' X 4 x'c-c Ho C=O t (V-g) The starting material represented by (IIB) is formylated under substantially similar conditions described for the first step in Reaction Scheme A, supra, except that the reaction is carried out at refluxing conditions The 21formylated steroid (IIIB) is the halogenated, that is chlorinated or brominated, by reacting the compound represented by formula (IIIB) with a suitable halogenating agent in an appropriate inert solvent at temperatures of about 0 to 100 C, depending on the reactants and solvents, to give the 21,21-dihalo steroid of formula (IVB) Suitable chlorinating agents include cupric chloride with lithium chloride, sulfuryl chloride, t-butyl hypochlorite, and the like, preferably cupric chloride with lithium chloride, while suitable brominating agents include cupric bromide, Nbromosuccunimide, bromine, and the like, preferably cupric bromide Appropriate solvents include O' (QI 6) 1,576,550 .= 00 dimethylformamide, ethyl acetate, chloroform and carbon tetracnlorine, ano may be used for either the chlorination or bromination.

If the 21,21-dichloro or 21,21-dibromo steroid is desired, then at least two molar equivalents of the chlorinating agent or brominating agent must be respectively used to give a compound represented by formula (IVB) wherein X 3 5 and X 4 ar both chloro or both bromo If, on the other hand, the 21-bromo21chloro-steroid is desired, the halogenation is carried out stepwise by first reacting about an equimolar amount of a chlorinating (or brominating) agent with a compound represented by formula (IIIB) to give a 21-chloro (or bromo) compound represented by formula (IIIC) and thereafter brominating (or chlorinating) the 10 resulting compound of formula (IIIC) to give (IVB) wherein X 3 is chloro and X 4 is bromo The resulting 21,21-dichloro-21-formyl; 21,21-dibromo-21-formyl; or 21bromo-21-chloro-21-formyl steroids may be purified by methods known in the art such as solvent extraction and evaporation, filtration and recrystallization.

The steroid represented by formula (IVB) is then deformylated according to 15 the procedure discussed hereinbefore in relation to Reaction Scheme A to form a 21,21 dihalo 16 a,17 a isopropylidenedioxypregna 1,4,9 ( 11) triene-3,20dione represented by formula (VB) This in turn is reacted according to procedures set forth supra to form A 1,4 steroids of this invention represented by formula (I) wherein X 3 and X 4 are independently chloro or bromo; the broken line between 20 C,-C 2 represents a double bond; and X' and X 2 are previously defined.

The A 4 steroids of this invention are then easily obtained by reducing the C,-C 2 double bond of the A 14 steroids using a suitable reducing agent such as hydrogen with an appropriate catalyst such as tris-(triphenylphosphine) chlororhodium in an acceptable inert solvent such as a mixture of benzene and ethanol 25 Such a reaction readily takes place at 0 to 50 C, with 20 to 25 C being preferred.

Alternatively, the A 4 steroids of this invention represented by formula (I) wherein the bond between C, and C 2 is a single bond may be prepared by first forming an ethylene ketal derivative of the A 4 '911 '1 analog of a compound represented by formula (II) or (IIB), viz 30 CH 2 F o; AJ ' C '2 3 0 O then going through the steps discussed hereinbefore in relation to Reaction Schemes A and B to arrive at the ethylene ketal derivatives represented by the formula <-H C-O X_,( 352 _ 35 21 's O -H 3 Qx) wherein 1 1 1,576,550 1 1 12 1,576,550 12 X, XI, X 2, X 3 and X 4 are defined previously These compounds are then hydrolyzed to form compounds of this invention The hydrolysis takes place under acidic conditions and is a procedure well documented in the art See for example chapter I by J F W Keana in "Steroid Reactions", edited by C Djerassi, Holden Day ( 1963) 5 The A 14 steroids may be prepared through the 3-ethylene ketal route by reacting the A 4901 "-3-ethylene ketal with 2,3-dichloro-5,6dicyanobenzoquinone (DDQ) according to the procedure discussed in chapter 6 of "Organic Reactions of Steroid Chemistry", supra.

The starting materials for the process aspects of this invention, namely those 10 compounds represented by formulae (II), (IIB), (Iha) and (l Ib), are known in the art and may be prepared according to representative preparations given hereafter.

Pharmaceutical Composition The novel steroids of this invention may be formulated with suitable pharmaceutical vehicles known in the art to form particularly effective topical, anti-inflam 15matory compositions Generally about O 001 %w to about 10 %w of the steroids defined herein before are combined with about 90 %w to about 99 999 %w suitable excipients which may include a pharmaceutically acceptable solvent and other pharmaceutically acceptable additives to form apharmaceutical formulation which may be applied topically 20 A pharmaceutically acceptable solvent is one which is substantially nontoxic and non-irritating under the conditions used and may be readily formulated into any of the classical drug formulations such as creams, ointments, lotions or gels.

Particularly suitable solvents include water, glycerine, propylene carbonate, and glycols such as 1,2-propylene diol (i e propylene glycol), 1,3-propylene diol, or 25 mixtures thereof; polyethylene glycol having a molecular weight of from 100 to 20,000; and dipropylene glycol; and mixtures of the aforementioned with each other.

A cream, topical, anti-inflammatory mixture may be-prepared as a semisolid emulsion of oil in water or water in oil A cream base formulation by definition is an 30 emulsion which is a two phase system with one liquid (for example fats or oils) being dispersed as small globules in another substance (e g a glycolwater solvent phase which may be employed as the primary solvent for the novel steroids of this invention) Typically the cream formulation may contain other than the solvent with the steroids therein, fatty alcohols, surfactants, mineral oil or petrolatum and 35 other typical pharmaceutical adjuvants such as anti-oxidants, antiseptics, or compatible adjuvants A typical cream base formulation is given in the following table.

Water/glycol mixture 50-99 ( 15 % or more glycol) 40 Fatty alcohol 1 20 Non-ionic Surfactant 0 10 Mineral Oil 0 10 Typical pharmaceutical adjuvants 0 5 Active ingredients 0 001 10 45 The fatty alcohol, non-ionic surfactant, and other adjuvants are discussed in U S.

Patent 3,934,013 issued January 20, 1976 to Poulsen.

The novel steroids of this invention may also be formulated as ointments A "classical" ointment is a semi-solid anhydrous composition which may contain mineral oil, white petrolatum, a suitable solvent such as a glycol and may include so propylene carbonate and other pharmaceutically suitable additives such as surfactants, for example Span (Trade Mark) and Tween (Trade Mark) or wool fat (lanolin), along with stabilizers such as antioxidants and other adjuvants as mentioned before.

13 1,576,550 13 Following is an example of a typical "classical" ointment base:

White petrolatum 40-94 Mineral Oil 5-20 Glycol solvent 1 15 Surfactant 0-10 5 Stabilizer 0 10 Active Ingredients 0001 100 Other suitable ointment base formulations which contain propylene carbonate are described in U S patents 4,017,615 issued April 12, 1977 Shastri et al entitled "Propylene Carbonate Ointment Vehicle" and 3,924,004 issued December 3, 1975 10 Chang et al entitled "Fatty Alcohol-Propylene Carbonate-Glycol Solvent Cream Vehicle" The following is an ointment base formulation containing propylene carbonate found to be particularly effective for the compositions of this invention:

Active Ingredients 0001 10 0 Propylene Carbonate I 10 15 Solvent I 10 Surfactant I 10 White Petrolatum 70-97 Suitable solvents, surfactants, stabilizers, etc are discussed in U S 3, 934,013.

above 20 A suitable "non-classical" anhydrous, water washable "ointment type" base is described in U S 3,592,930 to Katz and Neiman A representative composition of this invention utilizing such a base is as follows:

Glycol solvent 40-85 Fatty alcohol 15-45 25 Compatible plasticizer 0 15 Compatible coupling 0 15 Agent Penetrant 0 20 Active Ingredients 0001 100 30 The fatty alcohols which are suitable have been previously disclosed above in this specification and in U S 3,592,930.

Generally an inflammed condition in animals, particularly humans, is treated by contacting the inflamed area with an effective amount of the novel steroids of this invention, i e an amount sufficient to effect improvement of the inflamed 35 condition Preferably the steroids are first formulated to prepare a suitable pharmaceutical formulation, as discussed hereinbefore, which is then placed in contact with the inflamed area An effective amount will depend upon the particular condition and the animal receiving the treatment but will vary between 0 001 % O and 5 % by weight of the pharmaceutical composition and preferably will be 40 between 0 01 and 1 % by weight of the formulation Using these levels in the formulation, a therapeutically effective and non-toxic amount, i e enough to effect an anti-inflammatory response, but enough to harm the recipient, is applied to the inflamed area.

PREPARATION A 5 This Preparation sets forth a process for making a starting material of formula (II) wherein X is H The Preparation is based on the method set forth in U S.

3,053,838 to Fried The compound 21-hydroxy-16 a,17 a-isopropylidenedioxypregna-l,4,0 ( 11)triene-3,20-dione (a known compound, see M Heller, R H.

Lenhard, S Bernstein, "Steroids" 5, 615-35, 1965) is reacted with mesyl chloride 10 in the presence of an organic base such as pyridine to form the corresponding 21mesyl steroid This, in turn, is heated with potassium fluoride in ethylene glycol to form 21 -fluro 16 a,17 a-isopropylidenedioxypregna 1,4,9 ( 11)triene-3,20dione.

PREPARATION B A starting material of formula (II) wherein X is fluoro is known and may be 15 prepared as taught in U S 3,409,613 issued November 5 1968 to J H Fried.

PREPARATION C A starting material of formula (II) wherein X is chloro is prepared by following the procedure set forth in Preparation A but starting with 6 a-chloro-21hydroxy16 a,17 a-isopropylidenedioxypregna-1,4,9 ( 11 l)triene-3,20-dione This compound is 20 prepared from 21 -hydroxy-16 a,17 a-isopropylidenedioxypregna 1,4,9 ( 11) triene3,20-dione (a known compound which may be prepared by hydrogenating 21hydroxy 16 a,17 a-isopropylidenedioxypregna-1,4,9 ( 11)triene-3,20-dione with tris(triphenylphosphine)chlororhodium in benzene and ethanol) according to a method described by Ringold et al in J A C S 80, 6464 ( 1958) In the Ringold et al 25 method, the corresponding 21-acetate of the 3-ethoxy-16 a,17 a-isopropylidenedioxypregna-3,5,9 (l 1)triene-20-one is first prepared which is then reacted with N-chloro succinimide to form the 6/3-CI-A 49 "" steroid This, in turn, is converted to the 6 a-chloro A 4 Bl'U steroid using hydrochloric acidacetic acid This compound is then reacted with selenium dioxide to give the corresponding A 149141, 30 steroid The 21-acetate is hydrolyzed to give the desired 21-hydroxy-6 achloro 1,4 9 '1- steroid.

PREPARATION D The starting material of formula (IIB) wherein X is H is a known compound and may be prepared as taught in U S 3,167,546 issued January 26, 1965 to 35 Bernstein et al or in J Am Chem Soc 81, 4962 ( 1959).

PREPARATION E The starting material of formula (IIB) wherein X is f is prepared by reacting 6 a-fluoro 16 a,17 a-isopropylidenedioxypregna-4,9 ( 11)-diene-3,20-dione (a known compound, see U S 3,197,470 issued July 27, 1965 to Deghenghi et al) with selenium dioxide as taught in Ringold et al J A C S 80, 6464 ( 1958) 40 PREPARATION F The starting material of formula (IIB) wherein X is Cl is prepared by reacting 16 a, 1 7 a-isopropylidenedioxypregna-4,9 ( 11)-diene-3,20-dione (a known compound, see British Patent 881,501 issued November 1, 1961 to American Cyanamid Corp) according to the Ringold et al process of Preparation C 45 PREPARATION G The starting 3-ethylene ketals represented by formulae (I Ia) and (I Ib) are readily prepared by reacting the starting material made according to Preparation A-F with hydrogen in the presence of tris-(triphenylphosphine) chlororodium in a solvent of benzene and ethanol The resulting 3-keto-A 49 m} 1 steroid is then reacted with a mixture of dry benzene, ethylene glycol and p-toluenesulfinic acid 50 monohydrate at reflux conditions using a water separator The reaction mixture is then washed with aqueous sodium bicarbonate solution and water, dried and evaporated to dryness to yield a compound represented by formulae (I Ha) or (I Ib) which is recrystallized from acetone:hexane.

The following non-limiting examples are set forth to more fully describe the 55 process and compounds of the invention and teach one of skill in the art how to 1,576,550 I 1 j 15 make representative compounds These examples are illustative only and are not presented to limit the scope of the invention in any way.

Example I

This example illustrates a process for preparing 9 a,l l/p-dichloro-21,21difluoro16 a, 17 a-propylidenedioxypregna1,4-diene-3,20-diones 5 (a) Formylation A compound of formula (I) was formylated according to the following reaction scheme and procedure CH 2 F 0 I O 0 ( 1 p A F ' O O To an ice-cooled three neck flask equipped with a mechanical stirrer and 10 charged with 5 milliliters (ml) a freshly distilled isopropylcyclohexylamine and 50 ml of dry tetrahydrofuran (THF), was added 20 ml of 1 5 molar n-butyl lithium followed by a solution of 5 0 grams (g) of the steroid ( 1) in 10 ml of dry THF and ml of hexamethylphosphoric triamide (HMPA) After stirring under nitrogen at room temperature overnight, 5 0 ml of purified ethyl formate was added and is stirring continued for 4 more hours at room temperature The contents of the flask were poured into 250 ml of water and extracted with three 50 ml portions of CH 2 CI 2 The combined CH 2 CI 2 layers were extracted with three 50 ml portions of l,N Na OH solution which was combined with the previous aqueous layer The combined aqueous basic layers were acidified with concentrated HCI in the 20 presence of ice, and the white precipitate was extracted with CH 2 CI 2 ( 5 x 30 ml) The combined CH 2 C 12 extracts were washed with water, brine, dried over Mg SO 4 and evaporated to give a yellow solid ( 6 25 g) Recrystallization from acetonehexane gave a crystalline sample, mp 136-1380 C.

(b) Chlorination and (c) Deformylation 25 The compound of part (a), above is chlorinated and deformylated according to the following reaction scheme and procedure.

0 Ox O 0 F ( 2) FI H C FCL ( 3) 1,576,550 < c To a flask charged with 625 milligrams (mg) of Cu CI 2 ( 3 6 millimole) and 76 4 mg of Li CI ( 1 8 millimole) in 0 9 ml of DMF was added 500 mg of the hydroxymethylene steroid ( 2) The solution was heated with stirring to 40-50 C for 3 hours under N 2 then to 80 C for I hour The solution was partitioned between CH 2 CI 2 ( 30 ml) and water ( 50 ml) After extracting the aqueous layer with CH 2 CI 2 ( 3 x 20 ml.) the combined organic layers were washed with water, dried over Mg SO 4 and evaporated to give a solid ( 546 mg).

This crude solid was dissolved in ethanol ( 5 ml) and cooled to O C Barium hydroxide ( 500 mg) was added and the mixture was stirred at O C for 2 hours then partioned between 50 ml ice cooled 0 1 N HC 1 and CH 2 C 12 ( 30 ml) After 10 extracting the aqueous layer with CH 2 CI, ( 2 x 20 ml) the combined organic layers were washed with water, brine, dried over Mg SO and evaporated to dryness to give a solid ( 496 mg) Recrystallization from CH 2 C 12-cyclohexane gave a crystalline sample, mp 218-222 C.

(d) Fluorination 15 The compound of formula ( 3) was fluorinated to form the corresponding 6 a,21,21-trifluoro compound according to the following reaction scheme and procedure:

CH Fz 0 0 -( 4) F To a flask charged with 1 17 g of N(CH 3)4 F and 15 g of sulfolane and heated 20 to 75 C was added with stirring 550 mg of the 21-chloro-21-fluoro steroid ( 3) The solution was stirred under nitrogen (N 2) for about 1/2 hour maintaining the temperature at 75 C The contents of the flask were poured into 50 ml water, and extracted with three 50 ml portions benzene The combined benzene layers were washed with water, brine, dried over Mg SO 4 and evaporated to give 600 mg of a 25 brown solid which was purified by chromatography on 50 g of silica gel with ethyl acetate and hexane as eluting solvents, giving 314 mg of the pure crystalline product, mp 223-224 C.

(e) Dichlorination at 9 a/Ill A The compound of formula ( 4) was dichlorinated to form a product of formula 30 ( 5) according to the following reaction scheme and procedure:

CHF 2 CIL O ( 4) O O it 0 ( 5) The 21,21-difluoro steroid ( 4) ( 45 mg) was dissolved in 2 ml of a solution made by adding I ml of pyridine to 10 ml of CH 2 C 12 A stream of chlorine gas was bubbled through this solution for 4 minutes After diluting with 20 ml of CH 2 CI 2 this 35 solution was washed with dilute HCI, water, brine, dried over Mg SO 4 and evaporated to give a solid ( 52 mg) The product was purified by preparative thick layer chromatography on silica gel with ethyl acetate in hexane as developing solvent Recrystallization from acetone-hexane gave the analytical sample ( 24 mg), of 9 a,1 l/-dichloro-6 a 21,21-trifluoro-16 a,17 aisopropylidenedioxypregna 1,4 40 diene-3,20-dione; mp 240-245 C (decomposed).

1,576,550 Similarly by following steps (a) through (e) in this example but substituting 6 a-chloro-21 -fluoro 16 a, 17 a-isopropylidenedioxypregna 1,4,9 ( 11)triene-3,20dione and 21 -fluoro 16 a,17 a-isopropylidenedioxypregna 1,4,9 ( 11)-triene-3,20dione for 6 a,21 difluoro 16 at 17 a isopropylidenedioxypregfgna-1,4,9 (fl)-triene3,20-dione 5 (formula 1) in step (a) the corresponding 6 a-chloro and 6-unsubstituted compounds of this invention may be obtained.

Example 2

This example illustrates the preparation of 9 a, l/3,21-trichloro-21fluoro16 a, 17 a-isopropylidenedioxypregna1,4-diene-3,20-diones 10 (a) Formylation, (b) Chorination, and (c) Deformylation The procedure set forth in Example I, step (a)-(c) was followed to obtain 21chloro 6 a,21 difluoro 16 a, 17 ca-isopropylidenedioxypregna 1,49 ( 11)triene-3,20dione The resulting compound is treated according to the procedure of Example I, step (e) to give 9 a, 11 P,21-trichloro-6 a,21-difluoro-16 a,17 aisopropylidenedioxy 15 pregna-l,4-diene-3,20-dione, m p 235 C (decomposes).

Similarly, by following the above procedure of this example but substituting 6 a-chioro-21 -fluoro 16 a, 17 a-isopropylidenedioxypregna 1,4,9 ( 1 i)triene-3,20dione and 21-fluoro-16 a,17 a-isopropylidenedioxypregna-1,4,9 ( 11)-triene-3,20dione for 20 6 a,21 difluoro 16 a, 17 ca isopropylidenedioxypregna 1,4,9 ( 1 l)-triene3,20-dione (formula 1) of step (a), the corresponding 6 a-chloro and 6-unsubstituted compounds of this invention may be obtained.

Example 3

This example sets forth a process for preparing 21-chloro-9 a,21-difluoro 1/3hydroxy 16 ca, 17 a-isopropylidenedioxypregna 1,4-diene-3,20-dione of this 25 invention.

The compound represented by formula ( 3) was prepared as in Example I, steps (a)-(c) The compound, 21-chloro-9 p,11 lp-oxido-6 oa,21-difluoro-16 a,17 a-isopropylidenedioxypregna 1,4-diene-3,20-dione, was prepared according to the following reaction scheme and procedure: 30 0 X 0 C:H FCL & F F ( 6) F ( 6 a) A solution of the 21-chloro-21-fluoro steroid ( 3) ( 106 mg) in dioxane ( 1 2 ml) was cooled to 10 C Dibromantin ( 160 mg) was added, followed by 0 09 ml of a solution made by diluting 3 ml of 30 % HC 104 to 27 ml with water The temperature was maintained at 10 C for 4 hours with stirring 35 To the above solution was added 2 3 mi of isopropyl alcohol followed by 255 6 mg of potassium acetate (KOAC) The solution was heated at reflux overnight.

The reaction mixture was then poured into 100 ml of water, and extracted with 80 ml of benzene and chloroform ( 3 x 10 ml) The combined organic layers were washed with water ( 100 ml), Na HCO 3 ( 50 ml) and brine ( 50 ml), dried over Mg SO 4 40 and evaporated to dryness The crystalline residue ( 176 mg) was recrvstallized from methanol to give the 9/A,1 1 P-oxido derivative ( 6 a), mp 208 C.

The 9/3,11/3-oxido compound represented by formula ( 6) was then hydrofluorinated to give a compound of this invention according to the following reaction scheme and procedure 45 1,576,550 CHFCL ( 6) X OX 0 ^( 7) F Eight-tenths ( 0 8) ml of a hydrogen fluoride-urea complex was added to a sample of the epoxy steroid ( 6) ( 52 mg) in a polyethylene bottle The reaction mixture was stirred at room temperature for 3 hours and then poured into an ammonium hydroxide solution, ( 0 1 N, 20 ml) The product was extracted with three 120 ml 5 portions of CH 2 CI 2 and the combined CH 2 CI 2 extracts were washed with water, brine, dried over Mg SO 4 and evaporated to give a solid ( 35 mg) Recrystallization from ethanol gave 21-chloro-6 a,9 a,21-trifluoro-11 /-hydroxy-16 a, 17 aisopropylidenedioxypregna-1,4-diene-3,20-dione, mp 303 C (decomposed).

Similarly by following the procedure of this example but substituting for the 10 compound represented by formula ( 3), the following compounds:

6 a,21 -dichloro-21 -fluoro 16 a, 17 a-isopropylidenedioxypregna 1,4,9 ( 11)-triene3,20-dione; 21 -chloro-21 -fluoro 16 a, 17 a-isopropylidenedioxypregna 1,4,9 ( 11)triene-3,20dione, the corresponding compounds of this invention may be obtained 15 Example 4

This example sets forth a process for preparing 9 a,21,21-trifluoro-ll/phydroxy 16 a, 17 a-isopropylidenedioxypregna 1,4-diene-3,20-diones.

The compound represented by formula ( 4), namely 6 a,21,21-trifluoro-16 a, 17 aisopropylidenedioxypregna-1,4,9 ( 11)-triene-3,20-dione, was prepared as in Example 20 1, steps (a)-(d) The 9/3,11 a-epoxidation and subsequent hydrofluorination procedure set forth in Example 3 was followed to prepare 6 a,9 a,21,21tetrafluoro11 /-hydroxy l 6 a,17 a-isopropylidenedioxypregna 1,4-diene-3,20-dione, m p.

289 C (decomposed).

Similarly, by following the process of this example but substituting 6 achloro 25 21,21 -difluoro 16 a,17 a-isopropylidenedioxypregna 1,4,9 ( 11)-triene-3, 20-dione and 21,21-difluoro-16 a,17 a-isopropylidenedioxypregna 1,4,9 ( 11)-triene-3, 20-dione, for the compound represented by formula ( 4), the corresponding 6 a-chloro or 6unsubstituted compounds of this invention may be obtained.

Example 5 30

This example sets forth a procedure for preparing the 9 a-bromo 11/3hydroxyA 1,4 steroids of this invention In this process, the procedure for preparing a compound represented by formula ( 6) is followed, and after the compound represented by formula ( 3) is reacted with dibromantin and HC 104 for 4 hours at 10 C, the reaction mixture is poured into;ce water then extracted with methylene 35 chloride The organic phase is washed with water, aqueous Na HCO 3 and dried over Mg SO 4 The solvent is then evaporated and the product is recrystallized from ethanol to give 9 ca-bromo-21-chloro-6 a,21-difluoro l lp/-hydroxy-16 ca, 17 a-isopropylidenedioxypregna-1,4-diene-3,20-dione m p 218-220 C (decomposed).

Similarly by following the above procedure but substituting 6 a,21 dichloro-21 40 fluoro 16 a, 17 a-isopropylidenedioxypregna 1,4,9 ( 11)-triene-3,20-dione and 21chloro 21 fluoro 16 a, 17 a-isopropylidenedioxypregna 1,4,9 ( 1)-triene-3, 20-dione for the compound of formula ( 3), the corresponding 6 a-chloro and 6unsubstituted compounds are obtained.

Example 6 45

By following the procedure of Example 5 but substituting 6 a,21,21 trifluoro 16 a,17 a-isopropylidenedioxypregna 1,4,9 ( 11)triene-3,20dione, 6 a-chloro-21,21 -difluoro 16 a, 17 ca-isopropylidenedioxypregna 1,4,9 ( 11)-triene3,20-dione, 50 21,21 -difluoro 16 a, 17 a-isopropylidenedioxypregna 1,4,9 ( 11)-triene-3, 20-dione for the compound represented by formula ( 3), other corresponding compounds of this invention may be obtained.

1,576,550 Example 7

This example sets forth a procedure for preparing a 9 a-H-1 Iil-OH-A'4 steriod of this invention according to the following reaction scheme and procedure:

c(t CL e F -C-H F C-H F -G-H 0 ( 00 O, l ox 0 O F ( 6) ( 8) To a flask charged with 31 mg of tributyltin hydride in 15 ml of freshly 5 distilled THF is added 50 mg of the steroid ( 6) A trace amount of azobisisobutyronitrile is added to the vigorously stirred solution and the reaction flask is irradiated with a lamp After 1/2 hour the solvent is removed under vacuum and the product is extracted with 50 ml of CH 2 CI 2 The organic solution is washed with water, brine, dried over Mg SO 4 and evaporated to dryness to give a solid 10 Recrystallization from Me OH gives a crystalline product of 21-chloro-6 a, 21-difluoro 1 1-hydroxy 16 a,17 a-isopropylidenedioxypregna 1,4-diene-3,20dione.

Similarly, by substituting other 9 a-Br-l I/3-OH-A 1,4 steroids prepared according to Example 5 and Example 6, for the compound represented by formula ( 6), other 9 a-H 1/3-OH-A" 4 compounds of this invention may be prepared which correspond 15 to the respective starting compounds.

Example 8

The 9 a-chloro-llp/-OH-A 1 '4 steroids of this invention may be prepared by reacting a 9,11-oxido compound prepared according to Examples 3 and 4 with hydrogen chloride by well known procedures and isolated by procedures discussed 20 hereinbefore.

Example 9

This example sets forth a process for preparing the 9 a-11/3,21,21tetrachloroA" 4 steroids of this invention according to the following procedure Five g.

of 6 a-fluoro-16 a, 17 a-isopropylidenedioxypregna 1,4,9 ( 11)-triene-3, 20-dione is 25 formylated according to the procedure set forth in Example I except that once the ethyl formate is added stirring is continued at refluxing temperature for four more hours After extraction and isolation, recrystallization from acetone gave the corresponding 21-hydroxymethylene compound, m p 201 5-203 C This product was chlorinated and deformylated according to the procedure of Example 1 to give 30 21,21 dichloro 6 a fluoro 16 a, 17 a-isopropylidenedioxypregna 1,4,9 ( 11) -triene3,20-dione having a m p of 199 -200 C By following the dichlorination step of art (e) in Example I 9 a,1 l/3-21,21-tetrachloro-6 a-fluoro-16 a,17 aisopropylidenedioxypregna-1,4-diene-3,20-dione, m p 225-235 C (dec), is prepared.

Similarly, by substituting the appropriate 6 a-chloro or 6-unsubstituted 35 starting material for the 6 a-F-A" 49 '(") steroid in this example, other corresponding compounds of this invention are prepared.

Example 10

This example sets forth a process for preparing the 9 a-fluoro-I Iphydroxy21,21-dichloro-A 4 steroids of this invention The formylation, chlorination and de 40 formylation steps of Example 9 are followed and the 21,21-dichloro-A" 4911 " 1 steroid thus obtained is reacted according to the sequence of Example 3 to give the corresponding 21,21-dichloro 9 a,l l/p-bromohydrin and subsequent 9,11oxido steroid (m p 212 C-dec) which in turn is reacted with hydrogen fluoride as taught in Example 3 to give 21,21-dichloro-6 a,9 a-difluoro-ll/-hydroxy-16 a,17 a-iso 45 propylidenedioxypregna- 11,4-diene-3,20-dione, m p 270-285 C (dec).

1,576,550 1,576,550 20 Similarly, the corresponding 6 a-chloro and 6-unsubstituted compound are prepared by employing the appropriate starting material.

The intermediate 21,21-dichloro-9 a, 11/3-bromohydrins are prepared according to the process of Example 5 while the 9 a-hydrogen-11/-hydroxy compounds are prepared according to Example 7 The corresponding 21,21-dichloro-9 cr-CI 1/3 5 OH-At 4 steroids are prepared by following the procedures of Example 8.

Example 11

The 21,21 -dibromo compounds of this invention may be prepared by following the procedures of Examples 9 and 10 but dibrominating at 21 instead of dichlorinating 10 Example 12

The example sets forth a process for making the A 4 steroids of this invention.

CHFU C:O 00 ( 7) A solution of 25 mg of tris-(triphenylphosphine) chlororhodium in 6 ml of benzene and 15 ml of ethanol is stirred under hydrogen for 60 min The above 15 steroid ( 244 mg) is added and the resulting solution is stirred under hydrogen at room temperature and atmospheric pressure After hydrogen uptake is complete, the solution is evaporated to dryness and the residue taken up in a mixture of petroleum ether and methylene chloride The pure A 4 product corresponding to the A 1/4 compound ( 7) is isolated by column chromatography on silica gel 20 Similarly, by substituting other A" 14 steroids of this invention made according to Examples I-11 for the compound of formula ( 7), other corresponding A 4 steroids are prepared.

Example 13

An experiment was run to determine the acute toxicity of 9 a,11 p/3dichloro 25 6 a,21,21-trifluoro 16 a,17 a-isopropylidenedioxypregna 1,4-diene-3,20dione, i e.

the amount of drug which resulted in death of 50 percent of a test group of mice (LD 50).

Six Swiss-Webster mice (Simonsen Labs) weighing approximately 25 g each were administered the compound at a rate of 25 mg/kg/mouse in a carbomethoxy 30 cellulose vehicle on day I and were observed daily for mortality for 21 days thereafter None of the mice died The L Dso is, therefore, greater than 25 mg /kg.

for this compound.

Example 14

This example sets forth an assay for determining topical antiinflammatory 35 potential of the compounds of this invention.

A vasoconstriction assay was conducted by following a modification of the procedure of McKenzie, S W and Stoughton, R B "Method for Comparing Percutaneous Absorption of Steroids" Arch Dermat 86, 608 ( 1962).

Eight normal adult human subjects were treated on each forearm by topical 40 administration with alcoholic solutions containing I x 10-s and 1 x 10g/ml of each of the compounds to provide 64 total test sites for each compound in a series ( 32 for each concentration) Areas of the subjects forearms were outlined by a rubber stamp grid coated with silicone grease, and 10 lambda (microfibres) are applied per 7 x 7 mm square site After the preparations have dried, the areas on 45 each forearm are covered with Saran (Trade Mark) wrap and the margins sealed with tape The occlusive wrap is removed after 18 hours Twenty-four hours after 1,576,550 " 1 56502 application, the presence of vasoconstriction is noted by visual examination and expressed as the number of sites responding (vasoconstriction) The number of sites responding by vasoconstriction is calculated as a percentage of the total number of sites in Table I, below X, X', X 2, X 3 and X 4 refer to formula (I).

Table I

X Xi X 2 X 3 X 4 F Cl Cl F F I x 10-s g/mi.

% Sites I X 10-6 g/mi.

% Sites F F OH Cl Cl F Cl Cl Cl Cl F F OH F F F F OH Cl F F Br OH Cl F F Cl Cl F Cl Example 15

This example sets forth an assay for determining thymolitic activity of the compounds of this invention It is desirable to utilize topically applied cortico-steroids having minimal side effects such as thymolytic activity It has been found that the compounds of this invention have low thymolytic activity.

Intact male rats weighting 70-80 grams received subcutaneous injection of the test material in an aqueous vehicle daily for 2 days to determine thymolytic activity On the morning of the third day (at hour 0), the rats received the test material a third time The rats were sacrificed at hour 4, at which time both hind paws were removed and weighed separately and the thymus gland was also removed and weighed To determine thymolytic activity the mean thymus ratio (mg thymus weight/gram body weight) was calculated for each compound.

In each series the thymolytic potencies are calculated relative to hydrocortisone, i e hydrocortisone is arbitrarily given a value of one The total number of rats used and the respective dosages are given in Table II.

Table II

Total No.

X X 1 X 2 X 3 X 4 Rats Used F Cl Cl F F F OH F F F F Br OH CI F F Cl Cl F Cl F F OH CI Cl F Cl Cl Cl Cl F F OH Cl F Dosage Range Activity (mg) (vs Hydrocortisone = 1) 02- 18 Inactive (< 3) 005- 08 01- 16 02- 18 025- 4 005- 08 Inactive (< 3) < 3 < 3 < 2.5 < 13 Example 16

This experiment was run to determine the "skin-thinning", i e dermal atophy, potency of a compound of this invention vs triamcinolone acetonide, a known compound It is desirable to minimize the side effects of topically applied 25 1,576,550 22 1,576,550 22 corticosteroid as much as possible, for example dermal atrophy potency An assay using the rat was used to determine this effect and it was found that the compoundof this invention which was tested exhibits less dermal atrophy potency than commercially available triamcinolone acetonide.

Male albino rats (Sprague-Dawley derived, Simonsen Labs) weighing 170 + 10 5 g were lightly anesthetized with ether, shaved on the back and flanks with electric clippers, and for each rat, six bilaterally paired sites, three on each flank, were marked by intradermal injection of india ink The areas on the left flank served as solvent treated controls and received 10/1 of ethanol daily; the paired areas on the right flank received 10 pl of the appropriate concentration of test steroid in 10 ethanol Solvent and solutions were applied on days 1-S and 8-11 with reshaving as necessary Three animals, caged together without restraint, were used for each concentration of steroid, and individual body weights were determined on days 1, 5, 8 and 12.

On day 12, twenty-tour hours after the final applications, the animals were 15 killed and the full thickness skin from the shaved area was removed The skin was spread uniformly without stretching over a thin layer of water on a Teflon (Trade Mark), board, and 16 mm diameter circles centered over each tattoo mark were punched out Each plug was freed from adherent fat and muscle by scraping with a dull scalpel The plugs were blotted on lightly moistened filter paper and weighed to 20 the nearest milligram.

For chemical analyses, the plugs were dried at 100 for sixteen hours and broken into roughly equal pieces, each of which was weighed Hexosamine was assayed by hydrolyzing the sample in 5 ml of 4 NHCI at O IC O C for seventeen hours in tightly capped tubes After the tubes had cooled, 20 milligrams (mg) of 25 powdered charcoal were added to each, and after ten minutes the mixtures were filtered Duplicate 1 ml aliquots were then assayed for hexosamine according to the method of Boas (Boas NF:Method for the Determination of Hexosamines in Tissues, J Biol Chem, 204, 553-563,1953) For Hydroxyproline analysis, the samples were hydrolyzed in 3 ml of 6 N HCG at 125 C for 16-18 hours, evaporated 30 to dryness and redissolved in 3 ml water The samples were treated with charcoal ( 20 mgs), filtered, and aliquots of the filtrate were diluted for analysis of hydroxyproline content according to the method of Woessner (Woessner, J F, The Determination of Hydroxyproline in Tissues and Protein Samples containing Small Proportions of this Imino Acid, Arch Biochem Biophys, 93, 440-447, 35 1961).

Substantial differences in weight exist for the three plugs taken from the same flank Therefore, in the calculations, each treated plug was compared with its contralateral control, and the decrease was expressed as a percent of the control plug weight 40 The difference in values of hexosamine and hydroxyproline in the treated versus the untreated plugs indicates that there is less protein in the treated plugs, i.e the treated plugs have "thinned" compared to the untreated In the compound of this invention, this difference is less than triamcinolone acetonide, thus showing the compounds of this invention have less of a "skin thinning"effect In Table III, 45 triamcinoline acetonide is arbitrarily given the value of 1 while the compound of this invention is compared to the known compound the results show that the compound of this invention has less dermal atrophy potency than triamcinolone acetonide.

Table III

Compound Dermal Atrophy Potency Triamcinolone acetonide I X=F;X 1 =F;X 2 =OH;X 3 =CI;X 4 =C 1 0.4-0 7

Claims (2)

WHAT WE CLAIM IS:-

1.576,550 14 A method of treating an inflamed condition in non-human animals which comprises contacting the inflamed area on said animal with a therapeutically effective amount of a compound of claim

2.

A process for preparing 21,21-dihalosteroids, which process comprises (a) reacting a formylating agent with a compound of formula CH 2 F I c,12 r % O or 0 ' wherein X is fluoro, chloro or hydrogen, to form a compound of the formula FC=CHOH C= O wherein the wavy line represents the remainder of the steroid nucleus, identical to 10: that of the starting compound; (b) reacting the product compound of step (a) with a halogenating agent to form a compound of formula I F'- -L Ho C= O where X 4 is fluoro, chloro or bromo; (c) deformylating the product of step (b) to produce a compound of formula X 4 I I F-C-H I C=O (d) optionally reacting the product of step (c) in which X 4 is chloro or bromo with a fluorinating agent to produce a compound of formula F 2 Crdthen either 1,576,550 (e) reacting the product of step (c) or (d) with a chlorinating agent to produce a compound of the formuala a where the wavy lines represent the remainder of the steroid nucleus, identical to that of the starting compound; or (f) reacting the product of step (c) or (d) with dibromantin in dilute perchloric acid solution to form a compound of the formula X.

1 F-C-9 1 C= O -o O O where the wavy lines represent the remainder of the steroid nucleus, identical to that of the starting compound; (g) optionally dehydrobrominating the product of step (f) to form a compound of the formula X'f.

F-C-H l hug K followed by reaction with a hydrofluorinating or hydrochlorinating agent to form a compound of the formula F-4 -F-C-MH in which X' is fluoro or chloro; 1,576,550 r -, U (h) optionally reducing the product of step (f) to form a compound of the formula F-CA LtF I ' (i) optionally reducing a At,4 product of step (e), (f), (g) or (h) to produce the ' corresponding A 4 steroid; (j) hydrolysing a 3-ethylene ketal product of step (e), (f), (g) or (h) to produce the corresponding A 4-3-oxo steroid; (k) optionally reacting the A 4 steroid of step () with 2,3-dichloro-5,6dicyanobenzoquinone to produce the corresponding A 14 steroid.

16 A process for preparing 21,21-dihalo steroids, which process comprises (a) reacting a formylating agent with a compound of formula CH 3 or X wherein X is fluoro, chloro or hydrogen, to form a compound of the formula HF C=CHOH I c o where the wavy line represents the remainder of the steroid nucleus, identical with that of the starting compound; (b) chlorinating and/or brominating the product of step (a) to form a compound of formula X 4 xC O x 3 caa =o where each X 3 and X 4 is independently chloro or bromo; (c) deformylating the product of step (b) to form a compound of the formula 1.5576,550 1) 1 < 1,576,550 X 4 2 -C H V O x_ T then either (d) reacting the product of step (c) with a chlorinating agent to produce a compound of the formula a where the wavy lines represent the remainder of the steroid nucleus, identical to that of the starting compound; or (e) reacting the product of step (c) with dibromantin in dilute perchloric acid solution to form a compound of the formula where the wavy lines represent the remainder of the steroid nucleus, identical to that of the starting compound; (f) optionally dehydrobrominating the product of step (e) to form a compound of the formula X 4 o X-CX c-N followed by reaction with a hydrofluorinating or hydrochlorinating agent to form a compound of the formula 1 X+ = O HO in which X' is fluoro or chloro; (g) optionally reducing the product of step (e) to form a compound of the formula X-c-" C-OO 40 -: 5 (h) optionally reducing a A 14 product of step (d), (e), (f) or (g) to produce the corresponding a 4 steroid; (i) hydrolysing a 3-ethylene ketal product of step (d), (e), (f) or (g) to produce the corresponding A 4-3-oxo steroid; (j) optionally reacting the A 4 steroid of step (i) with 2,3-dichloro-5,6 10 dicyanobenzoquinone to produce the corresponding A 1 '4 steroid.

17 A process which comprises one or more of the following steps:

(a) hydrofluorinating or hydrochlorinating a compound of the formula X 3, C-e ó-H CO C I ox O -0 or or wherein X; X 3 and X 4 are defined in claim 1, to produce a compound of the formula 1,576,550 w&here X' is fluoro or chloro; and the wavy lines represent the remainder of the steroid nucleus, identical to that of the starting compound; followed by hydrolysis of the 3-ethylene ketal group, when present, to produce the corresponding A 4-3oxo steroid; (b) reducing a AA 4 steroid of formula I of claim I to produce the corresponding A 4 steroid; (c) chlorinating a compound of formula or X where X, X 3 and X 4 are defined in claim 1, to produce a compound of the formula X 1 jcsyg where X 3, X 4 and the wavy lines are as defined above; followed by hydrolysis of the 3-ethylene ketal group, when present, to produce the corresponding A 4-3oxo steroid; (d) reacting a starting compound defined in step (c) above with dibromantin in is dilute perchloric acid solution to form a compound of the formula (Le O ó R I C= O < o X where X 3, X 4 and the wavy lines are as defined above; followed by hydrolysis of the 3-ethylene ketal group, when present, to produce the corresponding A 4-3oxo steroid; (e) reducing a compound of the formula 1,576,550 1,576,550 ox r-O 1 as defined in step (d) above to produce a compound of the formula HO 14 0 -gx followed by hydrolysis of the 3-ethylene ketal group, when present, to produce the corresponding a 4-3-oxo steroid; (f) hydrolysing a compound of the formula X 3 C 4 where X, X', X 2, X 3, and X 4 are as defined in claim I to produce the corresponding A 4 steroid of formula (I) of claim 1; (g) reacting a A 4 steroid of formula (I) of claim I with 2,3-dichloro-5, 6dicyanobenzoquinone to produce the corresponding A 1 '4 steroid.

18 A compound of claim I as exemplified herein.

19 A process for preparing a compound of claim 1, substantially as described herein.

20 A compound of claiftn I whenever prepared by a process or any one of claims 15, 16, 17 and 19.

21 A pharmaceutical composition comprising a compound of any one of claims 3 to 10, 18 and 20, with a suitable pharmaceutical vehicle.

)I(II )ACI O 1 C= O 31 1,576,550 31 MEWBURN, ELLIS & CO, Chartered Patent Agents, 70/72 Chancery Lane, London, WC 2 A IAD.

Agents for the Applicants.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1980.

Published by the Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.

1 A compound represented by the formula X Lt 1 C l-X 3 (i) X I wherein X is hydrogen, fluoro, or chloro; 5 X' is hydrogen, fluoro, chloro or bromo; X 2 is hydroxy or may be chloro when X' is chloro; X 3 and X 4 are independently fluoro, chloro or bromo; and the broken line between C I and C-2 indicates that the bond between C-I and C-2 is a single or a double bond 10 2 The compound of Claim I wherein X 3 and X 4 are independently fluoro or chloro.

3 The compound of Claim 2 wherein X, XI, X 3 and X 4 are all fluoro; X 2 is hydroxy; and the bond between C-I and C-2 is a double bond; namely 6 a,9 a,21,21 tetrafluoro 11 A hydroxy- 16 a,17 aisopropylidfenedioxyprgia-l,4 15 diene-3,20-dione.

4 The compound of Claim 2 wherein X 4 is chloro; X, X' and X 3 are all fluoro; X 2 is hydroxy; and the bond between C-1 and C-2 is a double bond; namely, 21 chloro 6 a,9 a,21-trifluoro l lp-hydroxy 16 a,17 aisopropylidenedioxypregna1,4-diene-3,20-dione 20 The compound of Claim 2 wherein X 1, X 2 and X 3 are all chloro; X and X 4 are each fluoro; and the bond between C-I and C-2 is a double bond; namely, 9 a, 11 P/,21 trichloro 6 a,21 difluoro 16 a, 17 aisopropylidenedioxypregna 1,4-diene-3,20-dione.

6 The compound of Claim 2 wherein X' and X 2 are each chloro; X, X 3 and X 4 25 are all fluoro; and the bond between C-I 1 and C-2 is a double bond; namely, 9 a,11/3 dichloro 6 a,21,21 difluoro 16 a,17 a-isopropylidenedioxypregnal,4diene-3,20-dione.

7 The compound of Claim 2 wherein X and X 3 are each fluoro, X' is bromo, X 2 is hydroxy, X 4 is chloro and the bond between C-I 1 and C-2 is a double bond; 30 namely, 9 a bromo 21 chloro 6 a,21-difluoro-l/3 p-hydroxy-16 oc,17 a-isopropylidenedioxypregna 1,4-diene-3,20-dione.

8 The compound of Claim 2 wherein X, X 3 and X 4 are each fluoro, X' is bromo, X 2 is hydroxy and the bond between C-I and C-2 is a double bond; namely, 9 a-bromo-6 a,21,21-trifluoro 11/3-hydroxy-16 a,17 aisopropylidenedioxy 35 pregna 1,4-diene-3,20-dione.

9 The compound of Claim 2 wherein X is fluoro; X', X 2, X 3 and X 4 are each chloro; and the bond between C-I 1 and C-2 is a double bond; namely, 9 a, 11/3,21,21-tetrachloro-6 a-fluoro-16 a,17 aisopropylidenedioxypregna 1,4-diene3,20-dione, 40 The compound of Claim 2 wherein X and X' are fluoro, X 2 is hydroxy, X 3 and X 4 are each chloro and the bond between C-I 1 and C-2 is a double bond; namely 21,21 -dichloro-6 a,9 a-difluoro I 1/3-hydroxy 16 a,17 aisopropylidenedioxypregna I,4-diene-3,20-dione.

11 A topical anti-inflammatory, composition which comprises a compound of 45 claim 1 formulated with a suitable pharmaceutical vehicle.

12 A tropical anti-inflammatory composition which comprises a compound of claim 2 formulated with a suitable pharmaceutical vehicle.

13 A method of treating an inflamed condition in non-human animals which comprises contacting the inflamed area on said animal with a therapeutically 50 effective amount of a compound of claim 1.